Human respiratory syncytial virus (RSV) is the most important cause of virus mediated lower respiratory tract illness (LRI) in infants and children worldwide. In infants, ˜2,345 per 100,000 hospitalizations are attributable to RSV infection in the United States annually and RSV is one of the leading causes of morbidity/mortality second only to influenza virus (1). Although traditionally regarded as a pediatric pathogen, RSV can cause life-threatening pulmonary disease in bone marrow transplant recipients and immunocompromised patients (2, 3). Most RSV mediated severe disease and mortality occurs in infants younger than 2 years (4). Among the elderly, RSV is also a common cause of severe respiratory infections that requires hospitalization (4).
Although the importance of RSV as a respiratory pathogen has been recognized for over 50 years, a vaccine is not yet available because of several problems inherent in RSV vaccine development including the very young age of the target population, recurrent infections in spite of prior exposure, and history of enhanced disease in young children that were immunized with a formaldehyde inactivated RSV (FI-RSV) vaccine in the 1960s (3, 5). Subsequent studies with samples from these children showed poor functional antibody responses with low neutralization or fusion-inhibition titers (6, 7). There was also evidence for deposition of immune complexes in the small airways (8), however the mechanism of the FI-RSV vaccine induced enhanced disease is poorly understood. Animal models of the FI-RSV vaccine associated enhanced respiratory disease (VAERD) suggested a possible combination of poor functional antibody responses and Th2-biased hyper cytokine release leading to eosinophilic infiltration in the lungs (9, 10).
RSV live-attenuated vaccines (LAV) have a good safety record in infants. However, a recent RSV LAV candidate (rA2cp248/404/1030deltaSH) was found to be safe in infants but poorly immunogenic (11). New vaccine development efforts are now under way, using recombinant technologies, different cell substrates, and structure-based vaccine design (3). The RSV F glycoprotein (PFP-2) formulated in alum was evaluated in clinical trials and found to be well tolerated but only modestly immunogenic in adults, pregnant women, and in the elderly (12). A mixture of F, G, and M recombinant proteins was tested in subjects >65 years and was found to induce >4-fold increase in serum neutralizing activity in 58% of subjects with low pre-vaccine titers (13). Recently the structures of the F protective targets recognized by MAbs palivizumab and 101F, as well as the pre-fusion form of the F protein trimer were resolved, leading to structure based design of new F-based vaccines (14-16). A subunit vaccine based on the central conserved region of the G attachment surface glycoprotein was also developed as a RSV polypeptide with the albumin-binding domain from streptococcal protein G, produced in prokaryotic cells and formulated with an alum-based adjuvant. Despite promising results in murine models, challenge studies in rhesus macaques showed no reduction of viral loads, and studies in adults showed a relatively low capacity for inducing neutralizing antibodies (17, 18). An optimally effective RSV vaccine must protect against antigenically divergent groups A and B RSV strains.
Despite advances in the development of subunit vaccines, a need still exists to produce RSV vaccines that will provide protective immunity without the potential for disease enhancement. The present invention addresses these and other needs.